Radiation remains one of the most effective treatments for a wide variety of malignant cells; however, healthy cells of the bone marrow, hair follicle, epidermis and gastrointestinal tract are extremely sensitive to radiation cell death, limiting the effective use of this therapy for the treatment of cancer. Radiation gastrointestinal (GI) syndrome is a typical consequence of radiation disease and it is a major lethal toxicity that may occur after a radiation/nuclear incident. The possibility of a radiologic disaster by way of nuclear detonation or accident has long existed, however the threat of attack with a radiation dispersal device has increased the urgency for safe and effective medical radiation countermeasures (MRCs). The Project BioShield Act and Department of Health and Human Services estimate that an effective MRC mitigator must be effective even when administered 24 h after a nuclear disaster, as this represents the minimum time necessary to mobilize treatment to a significant portion of an urban population. The Radiation Gastrointestinal (GI) Syndrome (RGS) is a major lethal toxicity that involves destruction of the intestinal stem cell compartment within crypt/villus units, resulting in mucosal denudation, loss of nutrient adsorption and susceptibility to infection by resident bacterial flora. Clinically, RGS presents with anorexia, vomiting, diarrhea, dehydration, systemic infection, and in extreme cases, septic shock and death. Despite extensive study of the effects of radiation on normal tissue, no effective prophylactic or therapeutic mitigator of the Radiation GI Syndrome are available for first responders, military personnel, or remediation workers entering a contaminated area.
Hematopoietic stem cell transplantation (including bone marrow transplants, peripheral blood stem cell donations, and stem cells from umbilical cord blood) is another way to treat advanced cancer; however, tissue transplants frequently evoke a variety of immune responses in the host, which results in rejection of the graft and graft versus host disease (“GvHD”). GvHD is a type of T-cell-mediated autoimmune disease. Hematopoietic stem cell transplants, especially bone marrow transplants are currently used to treat a number of malignant and non-malignant diseases including acute and chronic leukemias, myelomas, solid tumors (R. J. Jones, Curr Opin Oncol 3 (2), 234 (1991); G. L. Phillips, Prog Clin Biol Res 354B, 171 (1990)), aplastic anemias and severe immunodeficiencies (R. P. Gale, R. E. Champlin, S. A. Feig et al., Ann Intern Med 95 (4), 477 (1981); G. M. Silber, J. A. Winkelstein, R. C. Moen et al., Clin Immunol Immunopathol 44 (3), 317 (1987)). The conditioning regimen required prior to transplantation, designed to ablate or suppress the patient's immune system, renders the patient susceptible to neoplastic relapse or infection.
Recent use of unrelated and HLA non-identical donors has unfortunately increased the incidence of GvHD. While removal of T-cells from the donor marrow graft ameliorates GvHD, this strategy increases graft failure rates and markedly diminishes the therapeutically-beneficial graft-versus-tumor effect. As such, overall survival does not improve. Further, despite strong pre-clinical data, attempts to improve GvHD outcomes by diminishing inflammatory cytokine action by adding TNF antagonists to corticosteroids, the standard of care for acute GvHD, has provided limited therapeutic benefit.
Thus, there is an urgent need for alternative strategies to reduce the incidence and severity of radiation disease, GI syndrome, GvHD and other autoimmune diseases where GI damage leads to morbidity/mortality from sepsis in an animal as well as conditions characterized by high levels of endothelial apoptosis.